Targeted therapies for inhibiting the growth of cancer cells or inducing apoptosis are urgently needed for effective rhabdomyosarcoma (RMS) treatment. However, identifying cancer-targeting compounds ...with few side effects, among the many potential compounds, is expensive and time-consuming. A computational approach to reduce the number of potential candidate drugs can facilitate the discovery of attractive lead compounds. To address this and obtain reliable predictions of novel cell-line-specific drugs, we apply prediction models that have the potential to improve drug discovery approaches for RMS treatment. The results of two prediction models were ensemble and validated via in vitro experiments. The computational models were trained using data extracted from the Genomics of Drug Sensitivity in Cancer database and tested on two RMS cell lines to select potential RMS drug candidates. Among 235 candidate drugs, 22 were selected following the result of the computational approach, and three candidate drugs were identified (NSC207895, vorinostat, and belinostat) that showed selective effectiveness in RMS cell lines in vitro via the induction of apoptosis. Our in vitro experiments have demonstrated that our proposed methods can effectively identify and repurpose drugs for treating RMS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Localized surface plasmon resonance (LSPR)-based biosensors have recently garnered increasing attention due to their potential to allow label-free, portable, low-cost, and real-time monitoring of ...diverse analytes. Recent developments in this technology have focused on biochemical markers in clinical and environmental settings coupled with advances in nanostructure technology. Therefore, this review focuses on the recent advances in LSPR-based biosensor technology for the detection of diverse chemicals and biomolecules. Moreover, we also provide recent examples of sensing strategies based on diverse nanostructure platforms, in addition to their advantages and limitations. Finally, this review discusses potential strategies for the development of biosensors with enhanced sensing performance.
Li metal, which has a high theoretical specific capacity and low redox potential, is considered to the most promising anode material for next‐generation Li ion‐based batteries. However, it also ...exhibits a disadvantageous solid electrolyte interphase (SEI) layer problem that needs to be resolved. Herein, an advanced separator composed of reduced graphene oxide fiber attached to aramid paper (rGOF‐A) is introduced. When rGOF‐A is applied, F− anions, generated from the decomposition of the LiPF6 electrolyte during the SEI layer formation process form semi‐ionic CF bonds along the surface of rGOF. As Li+ ions are plated, the “F‐doped” rGO surface induces the formation of LiF, which is known as a component of a chemically stable SEI, therefore it helps the Li metal anode to operate stably at a high current of 20 mA cm−2 with a high capacity of 20 mAh cm−2. The proposed rGOF‐A separator successfully achieves a stable SEI layer that could resolve the interfacial issues of the Li metal anode.
Reduced graphene oxide (rGO) fibers attached to aramid paper acts as a conductive frame which helps a solid electrolyte interphase (SEI) layer to grow stably in the confined fibers structure and induces a chemically stable SEI layer containing LiF. This functional separator dramatically improves the stability of a Li metal anode.
2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is a well‐known environmental contaminant that produces a wide variety of adverse effects in humans. Catalpol, a major bioactive compound enriched in the ...dried root of Rehmannia glutinosa, is a major iridoid glycoside that alleviates bone loss. However, the detailed mechanisms underlying the effects of catalpol remain unclear. The present study evaluated the effects of catalpol on TCDD‐induced cytotoxicity in osteoblastic MC3T3‐E1 cells. Catalpol inhibited TCDD‐induced reduction in cell viability and increases in apoptosis and autophagic activity in osteoblastic MC3T3‐E1 cells. Additionally, pretreatment with catalpol significantly decreased the nitric oxide and nitrite levels compared with a control in TCDD‐treated cells and significantly inhibited TCDD‐induced increases in the levels of cytochrome P450 1A1 and extracellular signal‐regulated kinase. Pretreatment with catalpol also effectively restored the expression of superoxide dismutase and extracellular signal‐regulated kinase 1 and significantly enhanced the expression of glutathione peroxidase 4 and osteoblast differentiation markers, including alkaline phosphatase and osterix. Taken together, these findings demonstrate that catalpol has preventive effects against TCDD‐induced damage in MC3T3‐E1 osteoblastic cells.
Catalpol inhibited TCDD‐induced reduction in cell viability and increases in apoptosis and autophagic activity in osteoblastic MC3T3‐E1 cells. Additionally, pretreatment with catalpol significantly decreased the NO and nitrite levels compared to a control in TCDD‐treated cells and significantly inhibited TCDD‐induced increases in the levels of CYP1A1 and ERK. Pretreatment with catalpol also effectively restored the expression of SOD and ERK1 and significantly enhanced the expression of GPx4 and osteoblast differentiation markers, including ALP and Osterix.
Background and Aims
Enhanced sympathetic nervous activation and peripheral vasodilation in end‐stage liver disease (ESLD) may limit the importance of left ventricular ejection fraction (LVEF) as an ...influential prognosticator. We sought to understand the LVEF and cardiac dimensions in ESLD patients in order to define the LVEF threshold to predict all‐cause mortality after liver transplantation (LT).
Approach and Results
Data were collected prospectively from the Asan LT Registry between 2008 and 2016, and outcomes were retrospectively reviewed. LVEF, end‐diastolic volume index (EDVI), and end‐diastolic elastance (Eed) were measured by preoperative echocardiography. Of 2,799 patients, 452 (16.2%) had LVEF ≤ 60%, with 29 (1.0%) having LVEF < 55% and 269 (9.6%) had LVEF ≥ 70%. Over a median of 5.4‐year follow‐up, 329 (11.8%) patients died: 104 (3.7%) died within 90 days. LVEF (range, 30%‐81%) was directly proportionate to Model for End‐stage Liver Disease (MELD) scores, an index of liver disease severity, in survivors but showed a fixed flat‐line pattern in nonsurvivors (interaction P = 0.004 between groups), with lower EDVI (P = 0.013) and higher Eed (P = 0.001) in the MELD ≥ 20 group. Patients with LVEF ≤ 60% had higher 90‐day (13% vs. 7.4%; log rank, P = 0.03) and median 5.4‐year (26.7% vs. 16.2%; log rank, P = 0.003) mortality rates in the MELD ≥ 20 group, respectively, compared to those with LVEF > 60%. Specifically, in the MELD > 35 group, median 5.4‐year mortality rate was 53.3% in patients with LVEF ≤ 60% versus 24% in those with LVEF > 60% (log rank P < 0.001). By contrast, mortality rates of LVEF ≤ 60% and > 60% were similar in the MELD < 20 group (log rank P = 0.817).
Conclusions
LVEF ≤ 60% is strongly associated with higher post‐LT mortality rates in the MELD ≥ 20 group, indicating the need to appraise both LVEF and liver disease severity simultaneously. Enhanced diastolic elastance with low EDVI provides insights into pathogenesis of low LVEF in nonsurvivors with MELD ≥ 20.
Methylglyoxal (MG) is associated with the pathogenesis of age- and diabetes-related complications. Spironolactone is a competitive antagonist of aldosterone that is widely employed in the treatment ...of hypertension and heart failure. This study examined the effects of spironolactone on MG-induced cellular dysfunction in MC3T3-E1 osteoblastic cells.
MC3T3-E1 cells were treated with spironolactone in the presence of MG. The mitochondrial function, bone formation activity, oxidative damage, inflammatory cytokines, glyoxalase I activity, and glutathione (GSH) were measured.
Pretreatment of MC3T3-E1 osteoblastic cells with spironolactone prevented MG-induced cell death, and improved bone formation activity. Spironolactone reduced MG-induced endoplasmic reticulum stress, production of intracellular reactive oxygen species, mitochondrial superoxides, cardiolipin peroxidation, and inflammatory cytokines. Pretreatment with spironolactone also increased the level of reduced GSH and the activity of glyoxalase I. MG induced mitochondrial dysfunction, but markers of mitochondrial biogenesis such as mitochondrial membrane potential, adenosine triphosphate, proliferator-activated receptor gamma coactivator 1α, and nitric oxide were significantly improved by treatment of spironolactone.
Spironolactone could prevent MG-induced cytotoxicity in MC3T3-E1 osteoblastic cells by reduction of oxidative stress. The oxidative stress reduction was explained by spironolactone's inhibition of advanced glycation end-product formation, restoring mitochondrial dysfunction, and anti-inflammatory effect.
2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) has various toxicological effects in adipose tissue. Evidence is accumulating that glabridin, a flavonoid extracted from licorice, has beneficial effects on ...the regulation of glucose homeostasis. In this study, we investigated whether glabridin suppresses TCDD‐induced loss of adipogenic action using 3T3‐L1 adipocytes as a cell culture model of wasting syndrome. Glabridin effectively suppressed TCDD‐induced loss of lipid accumulation in this model. Pretreating cells with glabridin increased the gene expression of not only the adipogenesis‐associated key transcription factors peroxisome proliferator‐activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha, but also lipoprotein lipase in the presence of TCDD. TCDD decreased insulin‐stimulated glucose uptake, which was effectively restored by pretreatment with glabridin. Glabridin also inhibited the TCDD‐driven decreased production of insulin receptor substrate 1 and glucose transporter 4. TCDD increased the production of mitochondrial superoxides, prostaglandin E2, phospholipase A2, cyclooxygenase‐1 and intracellular calcium concentrations, while reducing the production of PPARγ coactivator 1 alpha and glycolysis. However, glabridin treatment reduced these TCDD‐induced effects. We conclude that glabridin suppresses the TCDD‐induced loss of lipid accumulation in 3T3‐L1 adipocytes by regulating the levels of PPARγ, CCAAT/enhancer binding protein alpha, lipoprotein lipase, glucose uptake, prostaglandin E2 and energy metabolism. These results also provide in vitro evidence of the effects of glabridin on adipocyte metabolism, which suggests a protective effect against dioxin exposure in the development of insulin resistance and diabetes.
Glabridin suppresses the TCDD‐induced loss of lipid accumulation in 3T3‐L1 adipocytes by regulating the levels of PPARγ, CCAAT/enhancer binding protein alpha, lipoprotein lipase, glucose uptake, prostaglandin E2 and energy metabolism. These results provide in vitro evidence of the effects of glabridin on adipocyte metabolism, which suggests a protective effect against TCDD exposure in the development of insulin resistance and diabetes.
We aimed to determine if the severity of computed tomographic coronary angiography (CTCA)–diagnosed coronary artery disease (CAD) is associated with postliver transplantation (LT) myocardial ...infarction (MI) within 30 days and early mortality. We retrospectively evaluated 2118 consecutive patients who underwent CAD screening using CTCA. Post‐LT type‐2 MI, elicited by oxygen supply‐and‐demand mismatch within a month after LT, was assessed according to the severity of CTCA‐diagnosed CAD. Obstructive CAD (>50% narrowing, 9.2% prevalence) was identified in 21.7% of patients with 3 or more known CAD risk factors of the American Heart Association. Post‐LT MI occurred in 60 (2.8%) of total patients in whom 90‐day mortality rate was 16.7%. Rates of post‐LT MI were 2.1%, 3.1%, 3.4%, 4.3%, and 21.4% for normal, nonobstructive CAD, and 1‐, 2‐, and 3‐vessel obstructive CAD, respectively. Two‐vessel or 3‐vessel obstructive CAD showed a 4.9‐fold higher post‐LT MI risk compared to normal coronary vessels. The sensitivity and negative predictive value of obstructive CAD in detecting post‐LT MI were, respectively, 20% and 97.5%. In conclusion, negative CTCA finding in suspected patients can successfully exclude post‐LT MI, whereas proceeding with invasive angiography is needed to further risk‐stratify in patients with significant CTCA‐diagnosed CAD. Prognostic role of CTCA in predicting post‐LT MI needs further research.
Liver transplant recipients with noninvasive computed tomographic coronary angiography–diagnosed obstructive coronary artery disease and those with severe stenosis show occurrences of 6.2% and 8.9%, respectively, of post–liver transplant type 2 myocardial infarction, which results in 16.7% of 90‐day all‐cause mortality.
Summary MicroRNAs (miRNAs) play important roles in the development, differentiation, and function of different cell types and in the pathogenesis of various human diseases. miRNAs are differentially ...expressed in normal and cancer cells. The investigation of miRNA expression between healthy subjects and patients with osteosarcoma is crucial for future clinical trials. We performed miRNA microarray analysis on 8 formalin-fixed, paraffin-embedded osteosarcoma tissue samples. We confirmed the results of the microarray analysis using reverse transcription polymerase chain reaction. miRNA profiling of osteosarcoma tissue samples showed that expression of 10 miRNAs had increased 10-fold compared with normal controls. Among the 10 miRNAs, 3 miRNAs (miR-199b-5p, miR-338-3p, and miR-891a) were confirmed to have been up-regulated by reverse transcription polymerase chain reaction. After transfection of 4 osteosarcoma cell lines with miR-199b-5p inhibitor, the expression of Notch pathway components in the transfected cell lines was changed. These results revealed that miR-199b-5p plays a role in Notch signaling in osteosarcoma. Recently, the inhibition of Notch and HES1 signaling has been suggested as a potential therapeutic strategy to prevent metastasis in human osteosarcoma. Taken together with our results, we suggest that miR-199b-5p inhibitor may also be a therapeutic option for osteosarcoma.
Background & Aims
Early allograft dysfunction (EAD) is predictive of poor graft and patient survival following living donor liver transplantation (LDLT). Considering the impact of the inflammatory ...response on graft injury extent following LDLT, we investigated the association between neutrophil‐to‐lymphocyte ratio (NLR) and EAD, 1‐year graft failure, and mortality following LDLT, and compared it to C‐reactive protein (CRP), procalcitonin, platelet‐to‐lymphocyte ratio and the Glasgow prognostic score.
Methods
A total of 1960 consecutive adult LDLT recipients (1531/429 as development/validation cohort) were retrospectively evaluated. Cut‐offs were derived using the area under the receiver operating characteristic curve (AUROC), and multivariable regression and Cox proportional hazard analyses were performed.
Results
The risk of EAD increased proportionally with increasing NLR, and the NLR AUROC was 0.73, similar to CRP and procalcitonin and higher than the rest. NLR ≥ 2.85 (best cut‐off) showed a significantly higher EAD occurrence (20.5% vs 5.8%, P < 0.001), higher 1‐year graft failure (8.2% vs 4.9%, log‐rank P = 0.009) and higher 1‐year mortality (7% vs 4.5%, log‐rank P = 0.039). NLR ≥ 2.85 was an independent predictor of EAD (odds ratio, 1.89 1.26‐2.84, P = 0.002) after multivariable adjustment, whereas CRP and procalcitonin were not. Increasing NLR was independently associated with higher 1‐year graft failure and mortality (both P < 0.001). Consistent results in the validation cohort strengthened the prognostic value of NLR.
Conclusions
Preoperative NLR ≥ 2.85 predicted higher risk of EAD, 1‐year graft failure and 1‐year mortality following LDLT, and NLR was superior to other parameters, suggesting that preoperative NLR may be a practical index for predicting graft function following LDLT.
PDF
